Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Invest New Drugs. 2012 Oct;30(5):2066-79. doi: 10.1007/s10637-012-9796-8. Epub 2012 Feb 12.
Treatment of metastatic renal cell carcinoma (mRCC) has evolved rapidly over the last two decades as major pathways involved in pathogenesis have been elucidated. These include the vascular endothelial growth factor (VEGF) axis and mammalian target of rapamycin (mTOR). Therapies targeting the VEGF pathway include bevacizumab, sorafenib, sunitinib, pazopanib, and axitinib, whereas temsirolimus and everolimus inhibit the mTOR pathway. All of these novel therapies-VEGF and mTOR inhibitors-are associated with a variety of unique toxicities, some of which may necessitate expert medical management, treatment interruption, or dose reduction. Common adverse events with newer drugs include hypertension, skin reactions, gastrointestinal disturbances, thyroid dysfunction, and fatigue. Skilled management of these toxicities is vital to ensure optimal therapeutic dosing and maximize patient outcomes, including improved survival and quality of life. This review describes and compares the toxicity profiles of novel molecularly targeted agents used in the treatment of mRCC and presents guidance on how best to prevent and manage treatment-related toxicities. Particular attention is given to axitinib, the newest agent to enter the armamentarium. Axitinib is a second-generation receptor tyrosine kinase inhibitor with potent VEGF receptor inhibition that provides durable responses and superior progression-free survival in advanced RCC compared with sorafenib.
过去二十年中，转移性肾细胞癌（mRCC）的治疗方法取得了飞速发展，因为其发病机制中的主要途径已经得到阐明。这些途径包括血管内皮生长因子（VEGF）轴和哺乳动物雷帕霉素靶蛋白（mTOR）。针对 VEGF 途径的治疗方法包括贝伐珠单抗、索拉非尼、舒尼替尼、帕唑帕尼和阿昔替尼，而替西罗莫司和依维莫司则抑制 mTOR 途径。所有这些新型疗法——VEGF 和 mTOR 抑制剂——都与各种独特的毒性有关，其中一些可能需要专家进行医疗管理、治疗中断或剂量减少。新型药物的常见不良反应包括高血压、皮肤反应、胃肠道紊乱、甲状腺功能障碍和疲劳。熟练管理这些毒性对于确保最佳治疗剂量和最大限度地提高患者的治疗效果至关重要，包括提高生存率和生活质量。本文描述并比较了用于治疗 mRCC 的新型分子靶向药物的毒性特征，并就如何预防和管理治疗相关毒性提供了指导。特别关注的是阿昔替尼，这是最新进入治疗手段的药物。阿昔替尼是一种第二代受体酪氨酸激酶抑制剂，对 VEGF 受体具有强大的抑制作用，与索拉非尼相比，能为晚期 RCC 提供持久的反应和更好的无进展生存期。
